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PMID:21427722

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Citation

Nakamura, Y, Yamamoto, K, He, X, Otsuki, B, Kim, Y, Murao, H, Soeda, T, Tsumaki, N, Deng, JM, Zhang, Z, Behringer, RR, Crombrugghe, B, Postlethwait, JH, Warman, ML, Nakamura, T and Akiyama, H (2011) Wwp2 is essential for palatogenesis mediated by the interaction between Sox9 and mediator subunit 25. Nat Commun 2:251

Abstract

Sox9 is a direct transcriptional activator of cartilage-specific extracellular matrix genes and has essential roles in chondrogenesis. Mutations in or around the SOX9 gene cause campomelic dysplasia or Pierre Robin Sequence. However, Sox9-dependent transcriptional control in chondrogenesis remains largely unknown. Here we identify Wwp2 as a direct target of Sox9. Wwp2 interacts physically with Sox9 and is associated with Sox9 transcriptional activity via its nuclear translocation. A yeast two-hybrid screen using a cDNA library reveals that Wwp2 interacts with Med25, a component of the Mediator complex. The positive regulation of Sox9 transcriptional activity by Wwp2 is mediated by the binding between Sox9 and Med25. In zebrafish, morpholino-mediated knockdown of either wwp2 or med25 induces palatal malformation, which is comparable to that in sox9 mutants. These results provide evidence that the regulatory interaction between Sox9, Wwp2 and Med25 defines the Sox9 transcriptional mechanisms of chondrogenesis in the forming palate.

Links

PubMed Online version:10.1038/ncomms1242

Keywords

Animals; Campomelic Dysplasia/embryology; Campomelic Dysplasia/genetics; Campomelic Dysplasia/metabolism; Campomelic Dysplasia/pathology; Cartilage/embryology; Cartilage/metabolism; Cartilage/pathology; Cell Line; Chondrogenesis/drug effects; Chondrogenesis/genetics; Embryo, Mammalian/metabolism; Embryo, Mammalian/pathology; Embryo, Nonmammalian/metabolism; Embryo, Nonmammalian/pathology; Gene Expression Regulation; Gene Knockdown Techniques; Mediator Complex/deficiency; Mediator Complex/genetics; Mice; Mice, Transgenic; Morpholines/pharmacology; Mutation; Palate/drug effects; Palate/embryology; Palate/metabolism; Palate/pathology; Protein Binding; RNA, Small Interfering; Recombinant Proteins/genetics; Recombinant Proteins/metabolism; SOX9 Transcription Factor/genetics; SOX9 Transcription Factor/metabolism; Transcription, Genetic; Transcriptional Activation; Transfection; Two-Hybrid System Techniques; Ubiquitin-Protein Ligases/deficiency; Ubiquitin-Protein Ligases/genetics; Zebrafish

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

DANRE:A2VCZ7

located_in

GO:0005634: nucleus

ECO:0000250: sequence similarity evidence used in manual assertion

EMBL:BC048184

C

Seeded From UniProt

complete

DANRE:A2VCZ7

involved_in

GO:0060021: roof of mouth development

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-120518-3

P

Seeded From UniProt

complete

DANRE:E9QDH5

located_in

GO:0005634: nucleus

ECO:0000250: sequence similarity evidence used in manual assertion

EMBL:BC048184

C

Seeded From UniProt

complete

DANRE:E9QDH5

involved_in

GO:0060021: roof of mouth development

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-120518-3

P

Seeded From UniProt

complete

DANRE:E9QGN8

located_in

GO:0005634: nucleus

ECO:0000250: sequence similarity evidence used in manual assertion

EMBL:BC048184

C

Seeded From UniProt

complete

DANRE:E9QGN8

involved_in

GO:0060021: roof of mouth development

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-120518-3

P

Seeded From UniProt

complete

DANRE:F6P346

located_in

GO:0005634: nucleus

ECO:0000250: sequence similarity evidence used in manual assertion

EMBL:BC048184

C

Seeded From UniProt

complete

DANRE:F6P346

involved_in

GO:0060021: roof of mouth development

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-120518-3

P

Seeded From UniProt

complete

MOUSE:SOX9

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

PR:Q9DBH0

F

Seeded From UniProt

complete

MOUSE:SOX9

acts_upstream_of_or_within

GO:0034504: protein localization to nucleus

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:SOX9

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(CL:0000743)

Seeded From UniProt

complete

MOUSE:SOX9

enables

GO:0001228: DNA-binding transcription activator activity, RNA polymerase II-specific

ECO:0000314: direct assay evidence used in manual assertion

F

  • has_input:(MGI:MGI:1914144)

Seeded From UniProt

complete

MOUSE:SOX9

acts_upstream_of_or_within

GO:0045944: positive regulation of transcription by RNA polymerase II

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:1914144
MGI:MGI:1922863

P

  • occurs_in:(CL:0000743)
  • regulates_o_occurs_in:(CL:0000743)

Seeded From UniProt

complete

DANRE:MED25

involved_in

GO:0060021: roof of mouth development

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-120518-4

P

Seeded From UniProt

complete

MOUSE:MED25

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

PR:Q9DBH0

F

Seeded From UniProt

complete

MOUSE:MED25

part_of

GO:0005667: transcription regulator complex

ECO:0000353: physical interaction evidence used in manual assertion

PR:Q04887
PR:Q9DBH0

C

Seeded From UniProt

complete

MOUSE:MED25

acts_upstream_of_or_within

GO:0045944: positive regulation of transcription by RNA polymerase II

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:1914144
MGI:MGI:98371

P

  • occurs_in:(CL:0000743)
  • regulates_o_occurs_in:(CL:0000743)

Seeded From UniProt

complete

MOUSE:WWP2

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

PR:Q04887
PR:Q8VCB2

F

Seeded From UniProt

complete

MOUSE:WWP2

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(CL:0000743)

Seeded From UniProt

complete

MOUSE:WWP2

enables

GO:0061629: RNA polymerase II-specific DNA-binding transcription factor binding

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:98371

F

  • occurs_in:(CL:0000743)

Seeded From UniProt

complete

MOUSE:WWP2

part_of

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

part_of:(CL:0000743)

Seeded From UniProt

complete

MOUSE:WWP2

enables

GO:0001085: RNA polymerase II transcription factor binding

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:98371

F

occurs_in:(CL:0000743)

Seeded From UniProt

complete

MOUSE:WWP2

acts_upstream_of_or_within

GO:0045944: positive regulation of transcription by RNA polymerase II

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:1922863
MGI:MGI:98371

P

  • occurs_in:(CL:0000743)
  • regulates_o_occurs_in:(CL:0000743)

Seeded From UniProt

complete


See also

References

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